SWI/SNF is a multi-subunit chromatin remodeling complex that repositions nucleosomes to control access to DNA, thus regulating gene expression. Recently, we discovered focal DNA deletions and deleterious mutations that target SWI/SNF subunits in more than one-third of human pancreatic cancers, a frequency approaching that of TP53 mutation. SWI/SNF re-expression studies support a growth-suppressive function, and our preliminary data nominate polycomb repressive complex 2 (PRC2) antagonism and TGF signaling as possible downstream effector pathways. SWI/SNF has also been reported to function in DNA damage repair, and our preliminary data show SWI/SNF loss sensitizes pancreatic cells to DNA damage. Building from these findings, the broad goals of the proposed studies are to define the pathways and mechanisms by which SWI/SNF alterations contribute to pancreatic cancer, and to identify therapies that might selectively target SWI/SNF-deficient pancreatic cancers. To achieve these goals, in Aim 1 we will investigate the role of PRC2 antagonism as a mediator of SWI/SNF growth suppression, by molecular studies of PRC2 in SWI/SNF-deficient and reconstituted pancreatic cancer cells, and in primary pancreatic tumors. In Aim 2, we will similarly assess the role of TGF signaling in mediating SWI/SNF growth suppression. In Aim 3, we will determine whether residual SWI/SNF complexes (remnants of SWI/SNF alteration) contribute to growth phenotypes in pancreatic cancer cells. Finally, in Aim 4 we will evaluate possible therapies selective to SWI/SNF-deficient pancreatic cancers, starting with DNA damaging agents (to exploit the reported role of SWI/SNF in DNA damage repair) in cell viability assays. Completion of these studies should establish the pathways and mechanisms by which SWI/SNF alterations drive pancreatic cancer, and define therapeutic strategies for SWI/SNF-deficient pancreatic cancers. Given that SWI/SNF alterations are commonplace in pancreatic cancer, that almost nothing is known of their consequence (for example compared to TP53 mutations), and that pancreatic cancer is such a devastating disease, the proposed studies are expected to make a high-impact contribution to the field. Moreover, findings are likely to be extendable to other cancer types with SWI/SNF mutations.